title: Identification of prognostic protein biomarkers in childhood acute lymphoblastic leukemia (ALL).
abstract: Early response to 7 days of prednisolone (PRED) treatment is one of the important prognostic factors in predicting eventual outcome in childhood acute lymphoblastic leukemia (ALL). Using proteomic tools and clinically important leukemia cell lines (REH, 697, Sup-B15, RS4; 11), we have identified potential prognostic protein biomarkers as well as discovered promising regulators of PRED-induced apoptosis. After treatment with PRED, the four cell lines can be separated into resistant (REH) and sensitive (697, Sup-B15, RS4;11). Two dimensional gel electrophoresis (2-DE) and MALDI-TOF/TOF MS identified 77 and 17 significantly differentially expressed protein spots (p<0.05) in PRED-sensitive and PRED-resistant cell lines respectively. Several of these were validated by Western blot including proliferating cell nuclear antigen (PCNA), cofilin 1, voltage-dependent anion-channel protein 1 (VDAC1) and proteasome activator subunit 2 (PA28β). PCNA is a promising protein because of its important roles both in cell cycle regulation and survival control. We subsequently validated PCNA in 43 paired bone marrow samples from children with newly diagnosed ALL (Day 0) and 7 days after PRED treatment (Day 8). ROC curve analysis confirmed that PCNA was highly predictive of PRED response in patients (AUC=0.81, p=0.007) and most interestingly, independent of the molecular subtype, providing a promising universal prognostic marker.
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Shirley Kow Yin
authors.initials: SK
authors.lastname: Kham
authors.forename: Grace Shimin
authors.initials: GS
authors.lastname: Koh
authors.forename: Joshua Yew
authors.initials: JY
authors.lastname: Suang Lim
authors.forename: Hany
authors.initials: H
authors.lastname: Ariffin
authors.forename: Fook Tim
authors.initials: FT
authors.lastname: Chew
authors.forename: Allen Eng Juh
authors.initials: AE
authors.lastname: Yeoh
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D051338:Cofilin 1 / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011239:Prednisolone / Q000627:therapeutic use*; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D046988:Proteasome Endopeptidase Complex / Q000032:analysis; D040901:Proteomics / Q000379:methods; D050995:Voltage-Dependent Anion Channel 1 / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D051338:Cofilin 1; D018809:Proliferating Cell Nuclear Antigen; C494762:VDAC1 protein, human; D011239:Prednisolone; D050995:Voltage-Dependent Anion Channel 1; C486207:PSME2 protein, human; D046988:Proteasome Endopeptidase Complex